Medicine and Health Sciences Commons^™

Enterococcus Faecalis-Derived Adenine Enhances Enterohaemorrhagic Escherichia Coli Type 3 Secretion System-Dependent Virulence, Fernando H Martins, Thibaut Rosay, Anubama Rajan, Hannah E Carter, Tayah Turocy, Andres Mejia, Jason M Crawford, Anthony W Maresso, Vanessa Sperandio

Faculty, Staff and Students Publications

Interactions between microbiota and enteric pathogens can promote colonization resistance or enhance pathogenesis. The pathobiont Enterococcus faecalis increases enterohaemorrhagic E. coli (EHEC) virulence by upregulating Type 3 Secretion System (T3SS) expression, effector translocation, and attaching and effacing (AE) lesion formation on enterocytes, but the mechanisms underlying this remain unknown. Using co-infection of organoids, metabolomics, supplementation experiments and bacterial genetics, here we show that co-culture of EHEC with E. faecalis increases the xanthine-hypoxanthine pathway activity and adenine biosynthesis. Adenine or E. faecalis promoted T3SS gene expression, while transcriptomics showed upregulation of adeP expression, which encodes an adenine importer. Mechanistically, adenine relieved …

Disruption Of Fuz In Mouse Embryos Generates Hypoplastic Hindbrain Development And Reduced Cranial Nerve Ganglia, Carlo Donato Caiaffa, Yogeshwari S Ambekar, Manmohan Singh, Ying Linda Lin, Bogdan Wlodarczyk, Salavat R Aglyamov, Giuliano Scarcelli, Kirill V Larin, Richard H Finnell

Faculty, Staff and Students Publications

Background: The brain and spinal cord formation is initiated in the earliest stages of mammalian pregnancy in a highly organized process known as neurulation. Environmental or genetic interferences can impair neurulation, resulting in clinically significant birth defects known collectively as neural tube defects. The Fuz gene encodes a subunit of the CPLANE complex, a macromolecular planar polarity effector required for ciliogenesis. Ablation of Fuz in mouse embryos results in exencephaly and spina bifida, including dysmorphic craniofacial structures due to defective cilia formation and impaired Sonic Hedgehog signaling.

Results: We demonstrate that knocking Fuz out during embryonic mouse development results in …

Tauroursodeoxycholic Acid Ameliorates Renal Injury Induced By Col4a3 Mutation, Shuwen Yu, Teija Suhas, Meei-Hua Lin, Jeffrey H Miner, Et Al.

2020-Current year OA Pubs

COL4A3/A4/A5 mutations have been identified as critical causes of Alport syndrome and other genetic chronic kidney diseases. However, the underlying pathogenesis remains unclear, and specific treatments are lacking. Here, we constructed a transgenic Alport syndrome mouse model by generating a mutation (Col4a3 p.G799R) identified previously from one large Alport syndrome family into mice. We observed that the mutation caused a pathological decrease in intracellular and secreted collagen IV α3α4α5 heterotrimers. The mutant collagen IV α3 chains abnormally accumulated in the endoplasmic reticulum and exhibited defective secretion, leading to persistent endoplasmic reticulum stress in vivo and in vitro. RNA-seq analysis revealed …

Mutant Nrf2e79q Enhances The Promotion And Progression Of A Subset Of Oncogenic Ras Keratinocytes And Skin Tumors, John G Witherspoon, Jonathan R Hall, Dereje Jima, Hannah M Atkins, Nathan T Wamsley, Michael B Major, Bernard E Weissman, Robert C Smart

2020-Current year OA Pubs

Squamous cell carcinomas (SCCs), including lung, head & neck, bladder, and skin SCCs often display constitutive activation of the KEAP1-NRF2 pathway. Constitutive activation is achieved through multiple mechanisms, including activating mutations in NFE2L2 (NRF2). To determine the functional consequences of Nrf2 activation on skin SCC development, we assessed the effects of mutant Nrf2

Targeting Calpain-2-Mediated Junctophilin-2 Cleavage Delays Heart Failure Progression Following Myocardial Infarction, Satadru K Lahiri, Jiao Lu, Yuriana Aguilar-Sanchez, Hui Li, Lucia M Moreira, Mohit M Hulsurkar, Arielys Mendoza, Mara R Turkieltaub Paredes, Jose Alberto Navarro-Garcia, Elda Munivez, Brooke Horist, Oliver M Moore, Gunnar Weninger, Sören Brandenburg, Christof Lenz, Stephan E Lehnart, Rana Sayeed, George Krasopoulos, Vivek Srivastava, Lilei Zhang, Jason M Karch, Svetlana Reilly, Xander H T Wehrens

Faculty, Staff and Students Publications

Coronary heart disease (CHD) is a prevalent cardiac disease that causes over 370,000 deaths annually in the USA. In CHD, occlusion of a coronary artery causes ischemia of the cardiac muscle, which results in myocardial infarction (MI). Junctophilin-2 (JPH2) is a membrane protein that ensures efficient calcium handling and proper excitation-contraction coupling. Studies have identified loss of JPH2 due to calpain-mediated proteolysis as a key pathogenic event in ischemia-induced heart failure (HF). Our findings show that calpain-2-mediated JPH2 cleavage yields increased levels of a C-terminal cleaved peptide (JPH2-CTP) in patients with ischemic cardiomyopathy and mice with experimental MI. We created …

Transcriptional Coactivation Of Nrf2 Signaling In Cardiac Fibroblasts Promotes Resistance To Oxidative Stress, Lisa K Mcclendon, Rainer B Lanz, Anil Panigrahi, Kristan Gomez, Michael J Bolt, Min Liu, Fabio Stossi, Michael A Mancini, Clifford C Dacso, David M Lonard, Bert W O'Malley

Faculty, Staff and Students Publications

We recently discovered that steroid receptor coactivators (SRCs) SRCs-1, 2 and 3, are abundantly expressed in cardiac fibroblasts (CFs) and their activation with the SRC small molecule stimulator MCB-613 improves cardiac function and dramatically lowers pro-fibrotic signaling in CFs post-myocardial infarction. These findings suggest that CF-derived SRC activation could be beneficial in the mitigation of chronic heart failure after ischemic insult. However, the cardioprotective mechanisms by which CFs contribute to cardiac pathological remodeling are unclear. Here we present studies designed to identify the molecular and cellular circuitry that governs the anti-fibrotic effects of an MCB-613 derivative, MCB-613-10-1, in CFs. We …

Quantitative Gradient Recalled Echo (Qgre) Mri Enables In Vivo Measurement Of Pre-Atrophic Neurodegeneration In A Mouse Model Of Alzheimer's Disease, Michal R Tomaszewski, Alexander L Sukstanskii, Hyking Haley, Xiangjun Meng, Corin O Miller, Dmitriy A Yablonskiy

2020-Current year OA Pubs

Robust methods are needed for preclinical evaluation of novel Alzheimer Disease (AD) therapies to accelerate drug discovery. Quantitative Gradient Recalled Echo (qGRE) MRI has shown promise to provide insight into neurodegeneration in AD prior to atrophy development in humans, highlighting areas of low neuronal density. In this study a novel qGRE method (20 echoes, TE=2-40ms) is shown to non-invasively measure the longitudinal neuronal loss in the hippocampus of a mouse model of AD tauopathy Tg4510. Tg4510 (n=10) and wild type (WT, n=6) mice underwent MRI (7T field strength) at 3-7 months old. 3D qGRE approach was used to generate brain-specific …

Repeat Modules And N-Linked Glycans Define Structure And Antigenicity Of A Critical Enterotoxigenic E. Coli Adhesin, Zachary T. Berndsen, Marjahan Akhtar, Mahima Thapa, Tim J. Vickers, Aaron Schmitz, Pardeep Kumar, Nazia Khatoon, Alaullah Sheikh, Melissa Hamrick, Jackson S. Turner, Ali H. Ellebedy, James M. Fleckenstein, Et Al.

2020-Current year OA Pubs

Enterotoxigenic Escherichia coli (ETEC) cause hundreds of millions of cases of infectious diarrhea annually, predominantly in children from low-middle income regions. Notably, in children, as well as volunteers challenged with ETEC, diarrheal severity is significantly increased in blood group A (bgA) individuals. EtpA, is a secreted glycoprotein adhesin that functions as a blood group A lectin to promote critical interactions between ETEC and blood group A glycans on intestinal epithelia for effective bacterial adhesion and toxin delivery. EtpA is highly immunogenic resulting in robust antibody responses following natural infection and experimental challenge of volunteers with ETEC. To understand how EtpA …

Spatial Single-Cell Isotope Tracing Reveals Heterogeneity Of De Novo Fatty Acid Synthesis In Cancer, Elena Buglakova, Måns Ekelöf, Michaela Schwaiger-Haber, Lisa Schlicker, Martijn R Molenaar, Mohammed Shahraz, Lachlan Stuart, Andreas Eisenbarth, Volker Hilsenstein, Gary J Patti, Almut Schulze, Marteinn T Snaebjornsson, Theodore Alexandrov

2020-Current year OA Pubs

While heterogeneity is a key feature of cancer, understanding metabolic heterogeneity at the single-cell level remains a challenge. Here we present

Rhesus Rotavirus Nsp1 Mediates Extra-Intestinal Infection And Is A Contributing Factor For Biliary Obstruction, Enkai Li, Ningguo Feng, Qiru Zeng, Liliana Sanchez-Tacuba, Takahiro Kawagishi, Grace Branham, Gaopeng Hou, Zemin Wang, Harry B. Greenberg, Siyuan Ding

2020-Current year OA Pubs

We previously demonstrated that in Ifnar1-/-Ifngr1-/- or Stat1-/- suckling mice lacking intact type I and type II interferon (IFN) signaling, rhesus rotavirus (RRV) infection causes a lethal disease with clinical manifestations similar to biliary atresia, including acholic stools, oily fur, growth retardation, and excess mortality. Elevated levels of viral RNA are detected in the bile ducts and liver of diseased pups together with severe inflammatory responses in these tissues. However, the viral determinants and the molecular mechanisms driving this process remain incompletely understood. Using an optimized rotavirus (RV) reverse genetics system, we generated a panel of recombinant RVs that encode …

Regulatory Transposable Elements In The Encyclopedia Of Dna Elements, Alan Y Du, Jason D Chobirko, Xiaoyu Zhuo, Cédric Feschotte, Ting Wang

2020-Current year OA Pubs

Transposable elements (TEs) comprise ~50% of our genome, but knowledge of how TEs affect genome evolution remains incomplete. Leveraging ENCODE4 data, we provide the most comprehensive study to date of TE contributions to the regulatory genome. We find 236,181 (~25%) human candidate cis-regulatory elements (cCREs) are TE-derived, with over 90% lineage-specific since the human-mouse split, accounting for 8-36% of lineage-specific cCREs. Except for SINEs, cCRE-associated transcription factor (TF) motifs in TEs are derived from ancestral TE sequence more than expected by chance. We show that TEs may adopt similar regulatory activities of elements near their integration site. Since human-mouse divergence, …

Loss Of Periostin Function Impairs Ligament Fibroblast Activity And Facilitates Ros-Mediated Cellular Senescence, Muhammad Farooq Rai, Xin Duan, Mingming Yan, Robert H Brophy, Lei Cai

2020-Current year OA Pubs

Anterior cruciate ligament (ACL) injuries pose a significant challenge due to their limited healing potential, often resulting in premature arthritis. The factors and mechanisms contributing to this inadequate healing process remain elusive. During the acute phase of injury, ACL tissues express elevated periostin levels that decline over time. The functional significance of periostin in ligament biology remains understudied. In this study, we investigated the functional and mechanistic implications of periostin deficiency in ACL biology, utilizing ligament fibroblasts derived from patients and a murine model of ACL rupture. Our investigations unveiled that periostin knockdown compromised fibroblast growth characteristics, hindered the egress …

Stie: Single-Cell Level Deconvolution, Convolution, And Clustering In In Situ Capturing-Based Spatial Transcriptomics, Shijia Zhu, Naoto Kubota, Shidan Wang, Tao Wang, Guanghua Xiao, Yujin Hoshida

Faculty, Staff and Student Publications

In in situ capturing-based spatial transcriptomics, spots of the same size and printed at fixed locations cannot precisely capture the randomly-located single cells, therefore inherently failing to profile transcriptome at the single-cell level. To this end, we present STIE, an Expectation Maximization algorithm that aligns the spatial transcriptome to its matched histology image-based nuclear morphology and recovers missing cells from ~70% gap area, thereby achieving the real single-cell level and whole-slide scale deconvolution, convolution, and clustering for both low- and high-resolution spots. STIE characterizes cell-type-specific gene expression and demonstrates outperforming concordance with true cell-type-specific transcriptomic signatures than the other spot- …

Inhibition Of Ulk1/2 And Kras G12c Controls Tumor Growth In Preclinical Models Of Lung Cancer, Phaedra C Ghazi, Kayla T O'Toole, Sanjana Srinivas Boggaram, Michael T Scherzer, Mark R Silvis, Yun Zhang, Madhumita Bogdan, Bryan D Smith, Guillermina Lozano, Daniel L Flynn, Eric L Snyder, Conan G Kinsey, Martin Mcmahon

Faculty, Staff and Student Publications

Mutational activation of KRAS occurs commonly in lung carcinogenesis and, with the recent U.S. Food and Drug Administration approval of covalent inhibitors of KRASG12C such as sotorasib or adagrasib, KRAS oncoproteins are important pharmacological targets in non-small cell lung cancer (NSCLC). However, not all KRASG12C-driven NSCLCs respond to these inhibitors, and the emergence of drug resistance in those patients who do respond can be rapid and pleiotropic. Hence, based on a backbone of covalent inhibition of KRASG12C, efforts are underway to develop effective combination therapies. Here, we report that the inhibition of KRASG12C signaling increases autophagy in KRASG12C-expressing lung cancer …

Histone H3.3 Lysine 9 And 27 Control Repressive Chromatin At Cryptic Enhancers And Bivalent Promoters, Matteo Trovato, Daria Bunina, Umut Yildiz, Nadine Fernandez-Novel Marx, Michael Uckelmann, Vita Levina, Yekaterina Perez, Ana Janeva, Benjamin A Garcia, Chen Davidovich, Judith B Zaugg, Kyung-Min Noh

2020-Current year OA Pubs

Histone modifications are associated with distinct transcriptional states, but it is unclear whether they instruct gene expression. To investigate this, we mutate histone H3.3 K9 and K27 residues in mouse embryonic stem cells (mESCs). Here, we find that H3.3K9 is essential for controlling specific distal intergenic regions and for proper H3K27me3 deposition at promoters. The H3.3K9A mutation resulted in decreased H3K9me3 at regions encompassing endogenous retroviruses and induced a gain of H3K27ac and nascent transcription. These changes in the chromatin environment unleash cryptic enhancers, resulting in the activation of distinctive transcriptional programs and culminating in protein expression normally restricted to …

West Nile Virus Triggers Intestinal Dysmotility Via T Cell-Mediated Enteric Nervous System Injury, Hana Janova, Fang R. Zhao, Pritesh Desai, Matthias Mack, Larissa B. Thackray, Thaddeus S. Stappenbeck, Michael S. Diamond

2020-Current year OA Pubs

Intestinal dysmotility syndromes have been epidemiologically associated with several antecedent bacterial and viral infections. To model this phenotype, we previously infected mice with the neurotropic flavivirus West Nile virus (WNV) and demonstrated intestinal transit defects. Here, we found that within 1 week of WNV infection, enteric neurons and glia became damaged, resulting in sustained reductions of neuronal cells and their networks of connecting fibers. Using cell-depleting antibodies, adoptive transfer experiments, and mice lacking specific immune cells or immune functions, we show that infiltrating WNV-specific CD4+ and CD8+ T cells damaged the enteric nervous system (ENS) and glia, which led to …

Structural Basis For Mouse Lag3 Interactions With The Mhc Class Ii Molecule I-Ab, Qianqian Ming, Daniel Antfolk, David A Price, Anna Manturova, Elliot Medina, Srishti Singh, Charlotte Mason, Timothy H Tran, Keiran S M Smalley, Daisy W Leung, Vincent C Luca

2020-Current year OA Pubs

The immune checkpoint protein, Lymphocyte activation gene-3 (LAG3), binds Major Histocompatibility Complex Class II (MHC-II) and suppresses T cell activation. Despite the recent FDA approval of a LAG3 inhibitor for the treatment of melanoma, how LAG3 engages MHC-II on the cell surface remains poorly understood. Here, we determine the 3.84 Å-resolution structure of mouse LAG3 bound to the MHC-II molecule I-A

Cognitive Effects Of Simulated Galactic Cosmic Radiation Are Mediated By Apoe Status, Sex, And Environment In App Knock-In Mice, Laura Wieg, Jason C Ciola, Caroline C Wasén, Fidelia Gaba, Brianna R Colletti, Maren K Schroeder, Robert G Hinshaw, Millicent N Ekwudo, David M Holtzman, Takashi Saito, Hiroki Sasaguri, Takaomi C Saido, Laura M Cox, Cynthia A Lemere

2020-Current year OA Pubs

Cosmic radiation experienced during space travel may increase the risk of cognitive impairment. While simulated galactic cosmic radiation (GCRsim) has led to memory deficits in wildtype (WT) mice, it has not been investigated whether GCRsim in combination with genetic risk factors for Alzheimer's disease (AD) worsens memory further in aging mice. Here, we investigated the central nervous system (CNS) effects of 0 Gy (sham) or 0.75 Gy five-ion GCRsim or 2 Gy gamma radiation (IRR) in 14-month-old female and male APP

Adenovirus Vaccine Targeting Kinases Induces Potent Antitumor Immunity In Solid Tumors, Fei Zhu, Zheng Lu, Wenjing Tang, Guangya Zhao, Yingxiang Shao, Bowen Lu, Jiage Ding, Yanyan Zheng, Lin Fang, Huizhong Li, Gang Wang, Renjin Chen, Junnian Zheng, Dafei Chai

Faculty, Staff and Students Publications

BACKGROUND: Targeting kinases presents a potential strategy for treating solid tumors; however, the therapeutic potential of vaccines targeting kinases remains uncertain.

METHODS: Adenovirus (Ad) vaccines encoding Aurora kinase A (AURKA) or cyclin-dependent kinase 7 (CDK7) were developed, and their therapeutic potentials were investigated by various methods including western blot, flow cytometry, cytotoxic T lymphocyte assay, and enzyme-linked immunospot (ELISpot), in mouse and humanized solid tumor models.

RESULTS: Co-immunization with Ad-AURKA/CDK7 effectively prevented subcutaneous tumor growth in the Renca, RM-1, MC38, and Hepa1-6 tumor models. In therapeutic tumor models, Ad-AURKA/CDK7 treatment impeded tumor growth and increased immune cell infiltration. Administration of …

Diet-Induced Obesity Induces Transcriptomic Changes In Neuroimmunometabolic-Related Genes In The Striatum And Olfactory Bulb, Rosario B Jaime-Lara, Claudia Colina-Prisco, Marcel De Jesus Vega, Sarah Williams, Ted Usdin, Bridget Matikainen-Ankney, Alayna Kinkead, Brianna Brooks, Yupeng Wang, Alexis T Franks, Alexxai Kravitz, Paule V Joseph

2020-Current year OA Pubs

The incidence of obesity has markedly increased globally over the last several decades and is believed to be associated with the easier availability of energy-dense foods, including high-fat foods. The reinforcing hedonic properties of high-fat foods, including olfactory cues, activate reward centers in the brain, motivating eating behavior. Thus, there is a growing interest in the understanding of the genetic changes that occur in the brain that are associated with obesity and eating behavior. This growing interest has paralleled advances in genomic methods that enable transcriptomic-wide analyses. Here, we examined the transcriptomic-level differences in the olfactory bulb and striatum, regions …

Role Of Kindlin 2 In Prostate Cancer, Katarzyna Bialkowska, Lamyae El Khalki, Priyanka Rana, Wei Wang, Daniel Lindner, Yvonne Parker, Lucia Languino, Dario Altieri, Elzbieta Pluskota, Khalid Sossey-Alaoui, Edward Plow

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Kindlin-2 is a cytoskeletal adapter protein that is present in many different cell types. By virtue of its interaction with multiple binding partners, Kindlin-2 intercalates into numerous signaling pathways and cytoskeletal nodes. A specific interaction of Kindlin-2 that is of paramount importance in many cellular responses is its direct binding to the cytoplasmic tails of integrins, an interaction that controls many of the adhesive, migratory and signaling responses mediated by members of the integrin family of cell-surface heterodimers. Kindlin-2 is highly expressed in many cancers and is particularly prominent in prostate cancer cells. CRISPR/cas9 was used as a primary approach …

Whole Genome And Reverse Protein Phase Array Landscapes Of Patient Derived Osteosarcoma Xenograft Models, Chia-Chin Wu, Licai Huang, Zhongting Zhang, Zhenlin Ju, Xingzhi Song, E Anders Kolb, Wendong Zhang, Jonathan Gill, Min Ha, Malcolm A Smith, Peter Houghton, Christopher L Morton, Raushan Kurmasheva, John Maris, Yael Mosse, Yiling Lu, Richard Gorlick, P Andrew Futreal, Hannah C Beird

Faculty, Staff and Student Publications

Osteosarcoma is the most common primary bone malignancy in children and young adults, and it has few treatment options. As a result, there has been little improvement in survival outcomes in the past few decades. The need for models to test novel therapies is especially great in this disease since it is both rare and does not respond to most therapies. To address this, an NCI-funded consortium has characterized and utilized a panel of patient-derived xenograft models of osteosarcoma for drug testing. The exomes, transcriptomes, and copy number landscapes of these models have been presented previously. This study now adds …

Evaluating The Impact Of Laboratory-Based Eligibility Criteria By Race/Ethnicity In First-Line Clinical Trials Of Dlbcl, Arushi Khurana, Raphael Mwangi, Loretta J Nastoupil, Patrick M Reagan, Umar Farooq, Jason T Romancik, Timothy J Mcdonnell, Shaun M Riska, Lzidore S Lossos, Brad S Kahl, Peter Martin, Thomas E Witzig, James R Cerhan, Christopher R Flowers, Grzegorz S Nowakowski, Matthew J Maurer

Faculty, Staff and Student Publications

Underrepresentation of racial and ethnic subgroups in cancer clinical trials remains a persistent challenge. Restrictive clinical trial eligibility criteria have been shown to exacerbate this problem. We previously identified that up to 24% of patients treated with standard immunochemotherapy would have been excluded from recent first-line trials in diffuse large B-cell lymphoma (DLBCL) based on 5 laboratory-based criteria. These ineligible patients had worse clinical outcomes and increased deaths related to lymphoma progression, suggesting the potential exclusion of patients who could have benefited most from the novel therapies being evaluated. Using data from the prospectively enrolled Lymphoma Epidemiology Outcomes cohort study, …

Kmt2c Restricts G-Csf-Driven Hsc Mobilization And Granulocyte Production In A Methyltransferase-Independent Manner, Helen C Wang, Ran Chen, Wei Yang, Yanan Li, Rohini Muthukumar, Riddhi M Patel, Emily B Casey, Elisabeth Denby, Jeffrey A Magee

2020-Current year OA Pubs

Granulocyte colony-stimulating factor (G-CSF) is widely used to enhance myeloid recovery after chemotherapy and to mobilize hematopoietic stem cells (HSCs) for transplantation. Unfortunately, through the course of chemotherapy, cancer patients can acquire leukemogenic mutations that cause therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). This raises the question of whether therapeutic G-CSF might potentiate therapy-related MDS/AML by disproportionately stimulating mutant HSCs and other myeloid progenitors. A common mutation in therapy-related MDS/AML involves chromosome 7 deletions that inactivate many tumor suppressor genes, including KMT2C. Here, we show that Kmt2c deletions hypersensitize murine HSCs and myeloid progenitors to G-CSF, as evidenced …

Baf155 Controls Hematopoietic Differentiation And Regeneration Through Chromatin Priming, Jun Wu, Changxu Fan, Ashraf Ul Kabir, Karen Krchma, Minseo Kim, Yoojung Kwon, Xiaoyun Xing, Ting Wang, Kyunghee Choi

2020-Current year OA Pubs

Chromatin priming promotes cell-type-specific gene expression, lineage differentiation, and development. The mechanism of chromatin priming has not been fully understood. Here, we report that mouse hematopoietic stem and progenitor cells (HSPCs) lacking the Baf155 subunit of the BAF (BRG1/BRM-associated factor) chromatin remodeling complex produce a significantly reduced number of mature blood cells, leading to a failure of hematopoietic regeneration upon transplantation and 5-fluorouracil (5-FU) injury. Baf155-deficient HSPCs generate particularly fewer neutrophils, B cells, and CD8

Lung Cell Transplantation For Pulmonary Fibrosis, Irit Milman Krentsis, Yangxi Zheng, Chava Rosen, Sarah Y Shin, Christa Blagdon, Einav Shoshan, Yuan Qi, Jing Wang, Sandeep K Yadav, Esther Bachar Lustig, Elias Shetzen, Burton F Dickey, Harry Karmouty-Quintana, Yair Reisner

Faculty, Staff and Student Publications

Idiopathic pulmonary fibrosis is a major cause of death with few treatment options. Here, we demonstrate the therapeutic efficacy for lung fibrosis of adult lung cell transplantation using a single-cell suspension of the entire lung in two distinct mouse systems: bleomycin treatment and mice lacking telomeric repeat-binding factor 1 expression in alveolar type 2 (AT2) cells (SPC-Cre TRF1fl/fl), spontaneously developing fibrosis. In both models, the progression of fibrosis was associated with reduced levels of host lung progenitors, enabling engraftment of donor progenitors without any additional conditioning, in contrast to our previous studies. Two months after transplantation, engrafted progenitors …

Loss Of Symmetric Cell Division Of Apical Neural Progenitors Drives Dennd5a-Related Developmental And Epileptic Encephalopathy, Emily Banks, Vincent Francis, Sheng-Jia Lin, Fares Kharfallah, Vladimir Fonov, Maxime Lévesque, Chanshuai Han, Gopinath Kulasekaran, Marius Tuznik, Armin Bayati, Reem Al-Khater, Fowzan S Alkuraya, Loukas Argyriou, Meisam Babaei, Melanie Bahlo, Behnoosh Bakhshoodeh, Eileen Barr, Lauren Bartik, Mahmoud Bassiony, Miriam Bertrand, Dominique Braun, Rebecca Buchert, Mauro Budetta, Maxime Cadieux-Dion, Daniel G Calame, Heidi Cope, Donna Cushing, Stephanie Efthymiou, Marwa Abd Elmaksoud, Huda G El Said, Tawfiq Froukh, Harinder K Gill, Joseph G Gleeson, Laura Gogoll, Elaine S-Y Goh, Vykuntaraju K Gowda, Tobias B Haack, Mais O Hashem, Stefan Hauser, Trevor L Hoffman, Jacob S Hogue, Akimoto Hosokawa, Henry Houlden, Kevin Huang, Stephanie Huynh, Ehsan G Karimiani, Silke Kaulfuß, G Christoph Korenke, Amy Kritzer, Hane Lee, James R Lupski, Elysa J Marco, Kirsty Mcwalter, Arakel Minassian, Berge A Minassian, David Murphy, Juanita Neira-Fresneda, Hope Northrup, Denis M Nyaga, Barbara Oehl-Jaschkowitz, Matthew Osmond, Richard Person, Davut Pehlivan, Cassidy Petree, Lynette G Sadleir, Carol Saunders, Ludger Schoels, Vandana Shashi, Rebecca C Spillmann, Varunvenkat M Srinivasan, Paria N Torbati, Tulay Tos, Maha S Zaki, Dihong Zhou, Christiane Zweier, Jean-François Trempe, Thomas M Durcan, Ziv Gan-Or, Massimo Avoli, Cesar Alves, Gaurav K Varshney, Reza Maroofian, David A Rudko, Peter S Mcpherson

Faculty, Staff and Student Publications

Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells …

Early Rhombic Lip Protogenin+Ve Stem Cells In A Human-Specific Neurovascular Niche Initiate And Maintain Group 3 Medulloblastoma, Abhirami Visvanathan, Olivier Saulnier, Chuan Chen, Parthiv Haldipur, Wilda Orisme, Alberto Delaidelli, Seungmin Shin, Jake Millman, Andrew Bryant, Namal Abeysundara, Xujia Wu, Liam D Hendrikse, Vikas Patil, Zahedeh Bashardanesh, Joseph Golser, Bryn G Livingston, Takuma Nakashima, Yusuke Funakoshi, Winnie Ong, Alexandra Rasnitsyn, Kimberly A Aldinger, Cory M Richman, Randy Van Ommeren, John J Y Lee, Michelle Ly, Maria C Vladoiu, Kaitlin Kharas, Polina Balin, Anders W Erickson, Vernon Fong, Jiao Zhang, Raúl A Suárez, Hao Wang, Ning Huang, Jonelle G Pallota, Tajana Douglas, Joonas Haapasalo, Ferechte Razavi, Evelina Silvestri, Olga Sirbu, Samantha Worme, Michelle M Kameda-Smith, Xiaochong Wu, Craig Daniels, Antony K Michaelraj, Aparna Bhaduri, Daniel Schramek, Hiromichi Suzuki, Livia Garzia, Nabil Ahmed, Claudia L Kleinman, Lincoln D Stein, Peter Dirks, Christopher Dunham, Nada Jabado, Jeremy N Rich, Wei Li, Poul H Sorensen, Robert J Wechsler-Reya, William A Weiss, Kathleen J Millen, David W Ellison, Dimiter S Dimitrov, Michael D Taylor

Faculty, Staff and Students Publications

We identify a population of PRTG+ve MYChigh NESTINlow stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RLVZ). Oncogenic transformation of early Prtg+ve rhombic lip stem cells initiate Group 3 Medulloblastoma (Gr3-MB)-like tumors. PRTG+ve stem-cells grow adjacent to a human specific interposed vascular plexus in the RLVZ, a phenotype which is recapitulated in Gr3-MB, but not other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem-cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTGhigh compartment of Gr3-MB in vivo using either the diphtheria …

The Dna Repair Pathway As A Therapeutic Target To Synergize With Trastuzumab Deruxtecan In Her2-Targeted Antibody-Drug Conjugate-Resistant Her2-Overexpressing Breast Cancer, Jangsoon Lee, Kumiko Kida, Jiwon Koh, Huey Liu, Ganiraju C Manyam, Young Jin Gi, Dileep R Rampa, Asha S Multani, Jing Wang, Gitanjali Jayachandran, Dae-Won Lee, James M Reuben, Aysegul Sahin, Lei Huo, Debu Tripathy, Seock-Ah Im, Naoto T Ueno

Faculty, Staff and Student Publications

Background: Anti-HER2 therapies, including the HER2 antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), have led to improved survival outcomes in patients with HER2-overexpressing (HER2+) metastatic breast cancer. However, intrinsic or acquired resistance to anti-HER2-based therapies remains a clinical challenge in these patients, as there is no standard of care following disease progression. The purpose of this study was to elucidate the mechanisms of resistance to T-DM1 and T-DXd in HER2+ BC patients and preclinical models and identify targets whose inhibition enhances the antitumor activity of T-DXd in HER2-directed ADC-resistant HER2+ breast cancer in vitro and in vivo. …

The Role Of Gdf5 In Regulating Enthesopathy Development In The Hyp Mouse Model Of Xlh, Melissa Sorsby, Shaza Almardini, Ahmad Alayyat, Ashleigh Hughes, Shreya Venkat, Mansoor Rahman, Jiana Baker, Rakshya Rana, Vicki Rosen, Eva S Liu

Staff and Researcher Publications

X-linked hypophosphatemia (XLH) is caused by mutations in PHEX, leading to rickets and osteomalacia. Adults affected with XLH develop a mineralization of the bone-tendon attachment site (enthesis), called enthesopathy, which causes significant pain and impaired movement. Entheses in mice with XLH (Hyp) have enhanced bone morphogenetic protein (BMP) and Indian hedgehog (IHH) signaling. Treatment of Hyp mice with the BMP signaling blocker palovarotene attenuated BMP/IHH signaling in Hyp entheses, thus indicating that BMP signaling plays a pathogenic role in enthesopathy development and that IHH signaling is activated by BMP signaling in entheses. It was previously shown that mRNA expression of …